Isoprenaline-induced Changes Research Articles

The Possible Cardio-Reno- Protective Effects of Vanillin on Isopretrenol- Induced Myocardial Infarction in Rats

Myocardial infarction (MI) continues to be a major public health problem in the world. Vanillin is a natural phenolic compound that possesses significant anti-oxidant and anti-inflammatory activities. The present study aimed to investigate the effects of pretreatment with vanillin (150 mg/kg, p.o.) and vanillin (300 mg/kg, p.o.) on isoprenaline-induced MI in rats. Markers chosen to assess cardiac damage included serum activity of creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH), in addition to serum level of cardiac troponin-I (cTn-I), as well as antioxidant activity of cardiac catalase (CAT) as well as cardiac contents of RGH, lipid peroxides, and nitrite. Furthermore Electrocardiograph (ECG) monitoring and histological examinations of cardiac tissues were done. In addition markers chosen to assess renal impairment included serum and urine levels of creatinin, blood urea nitrogen (BUN), also creatinine clearance (Ccr), urea clearance (Ucr) and glomerular filteration rate (GFR) were assessed. In addition, antioxidant activity of renal CAT and renal contents of RGH, lipid peroxides, and nitrite. Furthermore, histological examinations of renal tissues were done. Isoprenaline increased serum CK-MB and LDH activity and cTn-I level, cardiac and renal oxidative stress biomarkers. In addition, it produced ST-segment elevation and degenerative changes in heart and renal tissues. Pretreatment with vanillin in previous doses significantly suppressed isoprenaline-induced pathological changes, as the elevated levels of cTn-I, LDH and CK-MB in serum coupled with reduction in cardiac and renal oxidative stress markers. Moreover marked improvement in ECG and histopathologic alterations in both cardiac and renal tissues were produced. In conclusion, vanillin can be regarded as a promising cardio- and reno- protective natural agent in MI.

Antioxidant defence of L-glutamine on mitochondrial function in experimentally induced myocardial infarction in rats

Myocardial infarction is a major public health concern and the leading cause of death all over the world. A better understanding of the processes involved in myocardial infarction has stimulated the search for biomolecules, which could limit the myocardial injury. We determined the protective activity of L-glutamine on mitochondrial function in isoprenaline-induced myocardial infarction in rats, an animal model of myocardial infarction in man. Oral pre-treatment with glutamine significantly inhibited the isoprenaline-induced changes in the levels of troponin T and homocysteine in the plasma. It conserved the activities of tricarboxylic acid cycle enzymes (isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, succinate dehydrogenase, malate dehydrogenase) and respiratory marker enzyme (NADH dehydrogenase) and the level of myocardial ATP content at levels comparable to that of normal controls. It also attenuated isoprenaline-induced oxidative stress in rat mitochondria and preserved the antioxidant defence system at near normal. The results indicate that the cardioprotective effect of glutamine can be correlated directly with its ability to activate the energy status and antioxidant defence system.Keywords: isoprenaline

Protective effects of atorvastatin and quercetin on isoprenaline-induced myocardial infarction in rats

Myocardial infarction (MI) continues to be a major public health problem in the world. Statins exhibit cardio-protective effects by several mechanisms beyond their lipid lowering activity. Quercetin is a natural flavonoid that possesses significant anti-oxidant and antiinflammatory activities. The present study aimed to investigate the effects of pretreatment with atorvastatin (10mg/kg) and quercetin (50mg/kg), as well as their combination on isoprenaline-induced MI in rats. Markers chosen to assess cardiac damage included serum activity of creatine kinase-MB (CK-MB) and serum level of cardiac troponin-I (cTn-I), as well as oxidative stress and inflammatory biomarkers including serum levels of C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), and interleukin-10 (IL-10) as well as cardiac contents of lipid peroxides, reduced glutathione (GSH), and nitrite. Furthermore, ECG monitoring and histological examinations of cardiac tissues were done. Isoprenaline increased serum CK-MB activity and cTn-I level as well as inflammatory and oxidative stress biomarkers. In addition, it produced ST-segment elevation and degenerative changes in heart tissues. Pretreatment with atorvastatin suppressed significantly the elevated levels of cTn-I, CRP, TNF-α, and IL-10 in serum coupled with reduction in cardiac lipid peroxides; however, it increased cardiac nitrite content. Quercetin decreased isoprenaline-induced changes in oxidative stress and inflammatory biomarkers with marked improvement in ECG and histopathologic alterations. Combination of quercetin with atorvastatin resulted in similar protective effects. In conclusion, quercetin can be regarded as a promising cardio-protective natural agent in MI alone or combined with atorvastatin.

Isoprenaline-induced changes in activity of the endogenous inhibitor of cAMP-dependent protein kinases under conditions of beta-adrenoceptor supersensitivity.

Isoprenaline-induced changes in activity of an endogenous, specific inhibitor of cAMP-dependent protein kinases (type I inhibitor) under conditions of experimental supersensitivity of beta-adrenoceptors were investigated in rat hippocampus and brain stem. Both subchronic administration of reserpine (2.5 mg kg-1, i.p., 4 days, once daily) and i.c.v injections of 6-hydroxydopamine (250 micrograms/ventricle, bilaterally, 48 h apart), which are known to increase beta-adrenoceptor sensitivity in the rat brain, markedly enhanced the response of the type I inhibitor activity to isoprenaline. To obtain a significant decrease of type I inhibitor activity in the examined brain structures of these animals, doses of isoprenaline 2-5 times lower than in control groups had to be used. It is suggested that the isoprenaline-induced decrease of type I inhibitor activity might be used as an index of central beta-adrenoceptor reactivity in-vivo.

Peripheral benzodiazepine receptor ligand Ro5-4864 inhibits isoprenaline-induced cardiac hypertrophy in rats

Oxidative stress plays a significant role in the pathogenesis of cardiac hypertrophy. Peripheral benzodiazepine receptors are ubiquitously expressed in various tissues, including the heart. Peripheral benzodiazepine receptors have been reported to be involved in the protection of cells against oxygen radical damage. The present study was designed to determine whether Ro5-4864 (a peripheral benzodiazepine receptor ligand) can inhibit isoprenaline-induced cardiac hypertrophy. Male Wistar rats (body weight 150–200g) were administered, isoprenaline (5mg/kg, body weight, subcutaneously) alone or along with Ro5-4864 (0.1 and 0.5mg/kg, body weight, intraperitoneally) once daily for 14days. Control rats received normal saline subcutaneously (1.0ml/kg). Isoprenaline-induced changes in heart weight to body weight ratio, left ventricular wall thickness (M-mode echocardiography and gross morphometry) and myocyte size were significantly prevented by both the doses of Ro5-4864. Ro5-4864 also attenuated isoprenaline-induced increase in interstitial fibrosis, lipid peroxidation and changes in endogenous antioxidants (glutathione, superoxide dismutase and catalase). Isoprenaline-induced cardiac hypertrophy was associated with increased expression of β myosin heavy chain, which was also prevented by Ro5-4864. This is the first study to demonstrate a salutary effect of Ro5-4864 in experimental cardiac hypertrophy.

Interaction between autoantibodies against the β 1-adrenoceptor and isoprenaline in enhancing L-type Ca 2+ current in rat ventricular myocytes

Autoantibodies against the β 1-adrenoceptor (β 1-AAB) in the serum of patients with dilated cardiomyopathy (DCM) are associated with stimulatory effects at cardiac β 1-adrenoceptors. They enhance cardiomyocyte shortening and increase the amplitude of L-type Ca 2+ current, I Ca . However, in contrast to the unselective β-adrenoceptor agonist (–)-isoprenaline, β 1-AAB produce positive responses in a fraction of myocytes (responder cells) only and fail to do so in the remaining ones (non-responder cells). To understand this peculiar behaviour, the electrophysiological characteristics of I Ca in response to β 1-AAB and (–)-isoprenaline were investigated in responder and non-responder cells. The immunoglobulin G (IgG) fractions containing β 1-AAB (β 1-IgG) were obtained from patients with DCM undergoing immunoabsorption therapy. Only antibody preparations that tested positive in the neonatal rat cardiomyocyte bio-assay by enhancing beating rate were used for further experimentation. Calcium currents were measured with the standard patch clamp technique in adult rat ventricular myocytes. Less than half of all cells exposed to β 1-IgG or purified β 1-AAB were responder cells in which I Ca amplitude increased. I Ca increase by β 1-IgG or (–)-isoprenaline was reversed by addition of carbachol. Exposure to subtype-selective β-adrenoceptor blockers indicated that the effects of IgG were mediated via β 1-adrenoceptors. In responder cells, there were no differences between β 1-IgG- and (–)-isoprenaline-induced changes in current-voltage relationship of I Ca , in the time constants of fast inactivation, and in steady-state activation and steady-state inactivation curves. (–)-Isoprenaline (1 μM) effectively increased I Ca after wash-out of antibody in all cells including non-responder cells. However, when non-responder cells were challenged with (–)-isoprenaline in the presence of β 1-IgG, any further increase in I Ca was completely suppressed. Conversely, in responder cells, the cumulative concentration-response curves for (–)-isoprenaline on top of the autoantibodies reached the same maximum I Ca amplitude as in control cells. From these interactions we conclude that β 1-AAB not only may enhance I Ca via stimulation of β 1-adrenoceptors but also may inhibit β 1-adrenoceptor-mediated increase upon stimulation with catecholamines suggesting a receptor interaction distinct from that with (–)-isoprenaline.

Differential effects of carvedilol and metoprolol on isoprenaline-induced changes in β-adrenoceptor density and systolic function in rat cardiac myocytes

beta-Blockers improve cardiac function and survival in heart failure patients. The underlying mechanisms are not completely elucidated. Differences between agents might be important for the development of more specific therapeutical approaches. This study investigated whether metoprolol or carvedilol alter beta-adrenergic signaling differently. beta-Adrenoceptor density and systolic function were determined in rat adult ventricular cardiac myocytes. 12 h isoprenaline-treatment (Iso, 1 micromol/l) reduced beta-adrenoceptor density by 33% (P<0.01). The effect was abolished by incubation with isoprenaline plus metoprolol (3 micromol/l), but was more pronounced after coincubation with carvedilol (0.003 micromol/l, P<0.05 Carv vs. Iso). Metoprolol alone had no effect on beta-adrenoceptor density, but carvedilol induced a decrease in receptor density even in absence of isoprenaline (P<0.05 Carv vs. ctr.). The isoprenaline (0.0003-10 micromol/l) induced concentration-dependent increase in myocyte shortening was blunted after 12 h preincubation with Iso (1 micromol/l, P<0.001). This reduction was abolished or partly prevented by coincubation with metoprolol or carvedilol, respectively. Carvedilol decreased the number of receptors which had to be occupied by isoprenaline in order to obtain 50% and 90% increase in myocyte cell shortening. Comparison of guanine nucleotide-dependent binding characteristics of isoprenaline, carvedilol and metoprolol revealed beta-receptor agonist like binding characteristics for carvedilol, but antagonist like binding characteristics for metoprolol. Metoprolol but not carvedilol prevents isoprenaline-induced downregulation of myocyte beta-adrenoceptors. The difference might be due to specific binding properties of the beta-blockers. Restoration of isoprenaline responsiveness by carvedilol might be due to improved coupling of beta-receptors to postreceptor effects.

Endurance training increases the beta-adrenergic lipolytic response in subcutaneous adipose tissue in obese subjects.

The aim of this study was to assess, by longitudinal follow-up, the influence of aerobic training on the in vivo lipolytic activity of adipose tissue in obese male subjects. Eleven obese non-diabetic males, aged 41.5+/-5.77 (range 27-49 y) with body mass index (BMI) 36.5+/-4.5 kg/m2 (range 29.4-47.1 kg/m2) participated in the study. Subjects took part in a 12-week aerobic training program. Before and after training, microdialysis of abdominal subcutaneous adipose tissue (SCAT) was carried out, using perfusion with graded doses of the beta-adrenergic agonist isoprenaline and a single dose of the phosphodiesterase inhibitor theophylline. In addition, the response of plasma glycerol and free fatty acids (FFAs) to intravenous infusion of graded doses of isoprenaline was tested. The training did not induce significant weight loss and promoted an increase in maximum aerobic capacity (P<0.05). The increase of extracellular glycerol in SCAT in response to isoprenaline perfusion was enhanced after the training (P<0.05), while no change in the response of interstitial glycerol to theophylline action was observed. The training did not elicit a change in the isoprenaline-induced changes of blood flow in adipose tissue. The increases of plasma FFAs and glycerol in response to intravenous isoprenaline infusion, were significantly enhanced after training. The present study shows that aerobic training induced an increase in the response of plasma and subcutaneous adipose tissue concentration of glycerol to beta-adrenergic stimulation. The effect of an agent acting at the post-receptor level (theophylline) in SCAT was not modified by training.

Effects of Flestolol, an Ultra-Short Acting β-Adrenoceptor Antagonist, on Hemodynamic Changes Produced by Treadmill Exercise or Isoprenaline Stimulation in Conscious Dogs

The beta-blocking activity of flestolol was established during increasing isoprenaline infusions and during graded physical exercise in conscious, chronically instrumented dogs. After a control cycle, flestolol was infused at three doses (1, 2.67, and 10 micrograms/kg/min). Flestolol has an extremely short half-life, demonstrated by an 83% loss of effect within 25 min. Thus, flestolol allows easy titration of the effect, which might be a valuable property for its use in the treatment of critically ill patients. Due to the difference between pure beta-adrenergic stimulation and the much more complex regulation of circulation during exercise, the hemodynamic response to flestolol elicited marked differences between both set ups. Flestolol shifted the dose-response curves of isoprenaline-induced changes in heart rate, positive left ventricular dp/dtmax, and diastolic arterial pressure dose dependently to the right, while its main effect during exercise was a decrease in positive left ventricular dP/dtmax. Thus, testing of beta-adrenoceptor blockers using isoprenaline-induced tachycardia leads to an overestimation of potency and therefore is not appropriate to predict the clinical efficacy of these drugs to prevent stress- or exercise-induced increases in heart rate and hence myocardial oxygen-demand.

Alterations in atrial reactivity in a strain of spontaneously diabetic rats

1. The present study examined the reactivity of atria from control and spontaneously diabetic rats to various adrenoceptor agonists and to adenosine. 2. Isoprenaline (1.5 nM-1500 nM) produced concentration-dependent increases in inotropy which were unchanged in diabetic atria. However, the sensitivity to isoprenaline-induced changes in chronotropy was reduced in diabetic preparations. 3. In the presence of propranolol (2 microM), phenylephrine (0.2 microM-100 microM) produced concentration-dependent increases in both inotropy and chronotropy; however, atria from diabetic rats exhibited a much greater maximal response. The diabetic state did not alter the sensitivity to phenylephrine. 4. Adenosine (0.15 microM-300 microM) produced concentration-dependent decreases in both inotropy and chronotropy which were unchanged in diabetic atria. 5. Radioligand binding studies revealed that both alpha 1- and beta-adrenoceptor populations were substantially reduced in atria from diabetic rats. However, there was no change in receptor affinity for either adrenoceptor. 6. These results show that diabetes leads to an alteration in atrial reactivity to adrenoceptor stimulation. Future studies examining steps following hormone-receptor coupling are required in order to characterize this defect.

Changes in regional blood flows and myocardial performance after administration of bisoprolol to pigs.

The cardioselective beta-adrenoceptor antagonist bisoprolol (4-1024 micrograms kg-1) caused in anaesthetized open-chest pigs a dose-dependent decrease in cardiac output, which was primarily due to a negative chronotropic action as heart rate decreased more than stroke volume. The decrease in stroke volume apparently resulted from a negative inotropic action of the drug, reflected by a decrease in max LV dP/dt in animals both with and without atrial pacing. A mild increase in systemic vascular resistance prevented serious hypotension. Pulmonary artery pressure was not affected, as pulmonary vascular resistance increased although the increase was statistically significant only with the highest concentration. The dose-related decreases in left ventricular blood flow were equally distributed over all myocardial layers and were the consequence of the reduced metabolic needs of the myocardium. Cerebral blood flow was well preserved but the changes in blood flow to some other organs and tissues (kidneys, stomach and skeletal muscle) paralleled that in cardiac output. The systemic haemodynamic effects of bisoprolol (16-1024 micrograms kg-1; i.v.) in conscious pigs resembled closely those observed in anaesthetised animals and were similar to those exerted by propanolol (25-300 micrograms kg-1; i.v.) in the same preparation. The effectiveness of bisoprolol and propranolol in antagonizing isoprenaline-induced changes in heart rate and max LV dP/dt were, however, markedly different. While propranolol inhibited both parameters to the same extent, bisoprolol was more effective in inhibiting max LV dP/dt than heart rate responses in conscious animals, probably due to beta 1-adrenoceptor selectivity.

A Comparison of the Cardioselectivity of Five β-Adrenoceptor Blocking Drugs

The cardioselectivities of five beta-adrenoceptor antagonists were compared. Six normal subjects received, in a double-blind random order, 200 mg acebutolol, 50 mg atenolol, 10 mg betaxolol, 100 mg metoprolol, 80 mg propranolol, and placebo. All beta-adrenoceptor antagonists produced a similar reduction in exercise tachycardia. Isoprenaline infusions in incremental doses were given. Dose-response curves were constructed and the doses of isoprenaline required to increase heart rate by 25 beats/min (I25), forearm blood flow by 3 ml/100 ml/min (IF3), and finger tremor by 200% (IT200), and decrease diastolic blood pressure by 25 mm Hg (ID25), after each treatment were compared. After propranolol, I25, ID25, IF3, and IT200 were greater (p less than 0.02) than after atenolol, betaxolol, and metoprolol; I25, ID25, and IT200 were greater than after acebutolol. After acebutolol I25, ID25, and IF3 were greater than after atenolol and betaxolol; IT200 was greater than after betaxolol. Atenolol and betaxolol caused less reduction in the isoprenaline-induced changes in blood glucose, plasma potassium, lactate, renin activity, and serum insulin than propranolol. Acebutolol caused less attenuation of blood glucose and plasma lactate, and metoprolol less attenuation of plasma renin activity, than propranolol. It is concluded that acebutolol, atenolol, betaxolol, and metoprolol cause less blockade of beta 2-adrenoceptors than propranolol, and atenolol and betaxolol are more cardioselective than acebutolol.

Effect of repeated electroconvulsive shocks on isoprenaline-induced changes of the endogenous inhibitor of cAMP-dependent protein kinase in rat brain

The effect of repeated electroconvulsive shocks (ECS) on the responsiveness to isoprenaline of an endogenous, specific inhibitor of cAMP-dependent protein kinase (type I inhibitor) was tested in rat hippocampus and brainstem. Isoprenaline produced a dose-dependent decrease in the type I inhibitor activity in these brain structures. Neither the basal activity nor the isoprenaline-induced changes of type I inhibitor activity were affected by a single ECS. However, a series of 11 ECS markedly reduced the response of the type I inhibitor activity to isoprenaline. The action of isoprenaline was completely blocked by propranolol and markedly enhanced by aminophylline. The results indicate that the subsensitivity of β-adrenoceptors is accompanied by reduced responsiveness of type I inhibitor activity to isoprenaline.

Effects of the beta 2-adrenoceptor antagonist ICI 118,551 on exercise tachycardia and isoprenaline-induced beta-adrenoceptor responses in man.

ICI 118,551, 5 to 80 mg orally, did not significantly alter resting heart rate or blood pressure. In doses less than 40 mg the reduction in exercise tachycardia was under 10 beats/min. ICI 118,551, 10 to 40 mg, did not appear to reduce the maximum rise in systolic pressure with isoprenaline but did attenuate the changes in diastolic pressure, forearm blood flow and finger tremor. It also attenuated the isoprenaline-induced changes in serum glucose, insulin and potassium. On these observed changes, the effect of ICI 118,551 20 mg was similar to that of 40 mg and of propranolol 10 mg, but greater than that of atenolol 25 mg. An isoprenaline tachycardia was attenuated by all doses of ICI 118,551 studied. After atropine (0.04 mg/kg) ICI 118,551 20 mg still significantly reduced the effects of isoprenaline suggesting that functional beta 2-adrenoceptors may be present in the human heart. In doses less than 40 mg, ICI 118,551 appears to be a selective and competitive antagonist of beta 2-adrenoceptors in man.

Isoprenaline-induced changes in rat parotid and submandibular glands are age- and dosage-dependent.

Neonatal rats treated with chronic injections of isoprenaline (isoproterenol) for 10 days revealed differential induction of proline-rich proteins and glycoprotein synthesis between the parotid and submandibular glands. Biosynthesis of proline-rich proteins (Mr 17000-35000) and a Mr-220000 glycoprotein were detectable by solubilization in 10%-trichloroacetic acid extracts from parotid glands 14 days after birth. The enzyme lactose synthase (UDP-galactose: 2-acetamido-2-deoxy-D-glucosamine 4 beta-galactosyltransferase) (EC 2.4.1.22) is also induced 4-7-fold in specific activity compared with control neonatal rats, but again only after 14 days post partum, with isoprenaline treatment. This is in accord with the ability of the parotid gland to respond to beta-receptor stimulation and subsequent increases in intracellular cyclic AMP necessary for induction of protein synthesis [Grand, Chong & Ryan (1975) Am. J. Physiol. 228, 608-612]. Induction of the proline-rich proteins and a Mr-190000 glycoprotein in the soluble fraction from the submandibular gland were not detected until 49 days after birth under identical conditions in the same animal. Cyclic AMP in the submandibular gland undergoes increases on beta-receptor stimulation similar to those achieved in the adult animal, 1 day after birth (Grand et al., 1975). This same differential induction between parotid and submandibular gland was obtained with a range of isoprenaline dosages in adult animals. Trichloroacetic acid-soluble proline-rich proteins were isolated from parotid glands at a dosage of 4.0 mg of isoprenaline/kg body wt., but 7.0 mg/kg was required to induce also biosynthesis of these proteins in the submandibular gland. Gland hypertrophy showed the same differential dosage kinetics, based on gland weight, between the two glands; however, hypertrophy could be accomplished at a lower dosage of isoprenaline than that used to induce proline-rich-protein biosynthesis.

Isoprenaline-induced secretion of active and inactive renin in anaesthetized rabbits and by kidney cortex slices.

1. The effect of the beta-adrenoceptor agonist isoprenaline on the secretion of active and inactive renin was investigated in two preparations. 2. In ten urethane-anaesthetized rabbits isoprenaline, given as a renal artery infusion, had relatively minor effects on renal sodium excretion (increased) and systemic arterial blood pressure (decreased). Urine volume, potassium excretion, creatinine clearance and serum electrolytes were all unchanged. Plasma active and inactive renin both increased immediately and returned to basal values after ceasing the isoprenaline infusion. 3. No significant changes in either plasma renin activity or renal function were observed in a group of ten control animals. 4. The magnitude of the isoprenaline-induced changes in plasma active renin was similar to that in a previous study of frusemide diuresis, but the time course was quite different. Inactive renin disappeared from plasma during frusemide diuresis. 5. Renin release by rabbit kidney cortex slices was also studied. Isoprenaline, added to the incubation medium, caused a dose-related increase in active renin secretion, but inactive renin release remained unchanged. This is in marked contrast to a previous study where reducing [Na+] increased active renin and inhibited inactive renin output. 6. These data support our previous suggestion that activation of inactive renin is regulated by a sodium-sensitive intrarenal mechanism.

Effect of amiloride on catecholamine-induced changes in ion transport in short-circuited frog skin

The effect of amiloride (10(-6) M), added either before or after the catecholamine, on the adrenaline- or isoprenaline-induced changes in short-circuit current and Na and Cl fluxes of isolated skin of Rana temporaria was investigated. At the catecholamine concentration used the increment in short-circuit was the same in the absence or presence of amiloride (ca. 7.1 neq.cm-2.min-1) and the amiloride inhibition was the same in the absence or presence of catecholamine (ca. 9.4 neq.cm-2.min-1). Amiloride inhibited the Na and Cl influxes of the control period (by --8.63 +/- 1.28 and --2.08 +/- 0.75 neq.cm-2.min-1, respectively) but did not prevent the increase of these fluxes on the addition of adrenaline. There was no evidence of amiloride inhibition of the Na and Cl effluxes. There was an association between the increase of Na efflux and net Cl efflux following adrenaline, which if secreted together by a neutral NaCl pump would not contribute to the increased short-circuit current. The increased short-circuit current was correlated with the increased Na influx throughout the experiment if allowance is made for the periods where there is a lag between the current and isotopic measurement (i.e., the period immediately after the addition of a drug). It is tentatively suggested that the catecholamine-induced increase in Na influx is not altered by the amiloride concentration used in this study. In addition the magnitude of the changes induced by catecholamine in the influx and efflux of both Na and Cl seem to be unaffected.

BETA-BLOCKADE AND BLOOD-LEVELS AFTER LOW-DOSE ORAL PROPRANOLOL: THE HEPATIC "FIRST-PASS" THRESHOLD REVISITED

Heart-rate, arterial pressure, and plasma-renin activity were determined in six normal subjects at rest and after an injection of 8 μg isoprenaline with and without prior propranolol administered orally in a dose of 5 mg 8-hourly for a total of five doses. After propranolol, resting heart-rate, systolic pressure, and plasma-renin activity all fell significantly (p<0≑05 to <0≑01). When the isoprenaline-induced changes of heart-rate, diastolic pressure, and plasma-renin activity without propranolol were compared to those with propranolol, these responses were greatly diminished (p<0≑01 to <0≑001). The percent blockade by propranolol of the isoprenaline-induced changes ranged from 65% for diastolic pressure to 77% for heart-rate and 78% for plasma-renin acitvity. Propranolol levels determined by conventional fluorometry were below accurate detection limits, whereas those determined by gas-liquid chromatography ranged from 2≑3 to 8≑5 ng/ml. These findings, which demonstrate beta-blockade with low-dose propranolol, are not consistent with the existence of a postulated threshold for the hepatic “first-pass effect” in man, which is said to require saturation by single doses of 30 mg or more before propranolol enters the systemic circulation.

Blockade of isoprenaline-induced changes in plasma free fatty acids, immunoreactive insulin levels and plasma renin activity in healthy human subjects, by propranolol, pindolol, practolol, atenolol, metoprolol and acebutolol.

Abstract 1 The effects of intravenously administered propranolol 0.01 and 0.03, pindolol 0.001 and 0.003, practolol 0.12 and 0.36, atenolol 0.03 and 0.09, metoprolol 0.045 and 0.135 and acebutolol 0.12 and 0.36 mg/kg, on isoprenaline-induced changes in heart rate, blood pressure, plasma free fatty acids, immunoreactive insulin plasma levels and plasma renin activity were determined in six healthy human subjects. 2 Propranolol, atenolol and metoprolol had a stronger effect on resting heart rate than practolol, acebutolol and pindolol, probably reflecting differences in intrinsic β-sympathomimetic activity. Antagonist potencies against isoprenaline-induced changes in heart rate and blood pressure suggested cardioselectivity for practolol, atenolol, metoprolol and the lower dose of acebutolol and non-cardioselectivity for propranolol, pindolol and the higher dose of acebutolol. 3 All six β-adrenoceptor blocking agents were able, to a varying extent, to antagonize the isoprenaline-induced increases in plasma free fatty acids and plasma immunoreactive insulin levels. In general, the cardioselective agents were relatively less effective antagonists than the non-cardioselective agents. 4 Resting plasma renin activity was reduced by all six β-adrenoceptor blocking agents, suggestive of the presence of β1-adrenoceptors mediating renin release, but the non-cardioselective agents propranolol and pindolol seemed relatively more effective in antagonizing isoprenaline-induced increases in plasma renin activity than the cardioselective agents, which indicates that β2-adrenoceptors might also be involved. 5 The results are compatible with the hypothesis that both β1- and β2-adrenoceptors are involved in the regulation of lipolysis, insulin release and renin release.

Comparative dromotropic activity of timolol and propranolol in anesthetized dogs

The comparative dromotropic activity of timolol (TML) and propranolol (PPL) was studies by means of His bundle electrograms in two groups of pentobarbital-anesthetized dogs: group I, non-atropinized dogs; group II, 8 atropinized dogs. β-Blocking agents were injected in 4 cumulative doses in each dog at 3 days' interval. The effects upon the heart rate (HR), and A-V nodal (AH), His—Purkinje (HV) and intraventricular (QS) conduction times were measured. The dromotropic effects of PPL and TML during atrial electrical stimulation and their effects upon chronotropic and dromotropic isoprenaline-induced changes were compared. TML exerted a 9–10 times moren potent negative chronotropic effect than PPL and a 4–5 times more potent negative dromotropic effect than PPL on AH conduction time. PPL and TML increased the duration of HV only in higher doses. This effect which was not modified by isoprenaline may be related to their membrane depressant effect. Neither TML, nor PPL nor isoprenaline modified QS duration. TML was 25 times more potent than PPL to antagonized the chronotropic action of isoprenaline and 11–18 times more potent than PPL to antagonizem the dromotropic action of isoprenaline upon AH. Parasympathic blockade with atropine did not modify the negative dromotropic activity of PPL and TML but modified their chronotropic effects.